Abstract
Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.
Highlights
Cannabis consumption especially in early adolescence [1], a period of increased vulnerability to its effects, increases the risk of developing schizophrenia [2]
Chronic THC potentiates (±)-DOI-induced decrease in prepulse inhibition (PPI) Loss of PPI in rodents is considered a valid proxy for the study of the neurobiology of impaired sensorimotor gating in schizophrenia patients [20, 21]
Several pharmacological and behavioral effects of THC have been well documented in animal models, little is known about the mechanism that promote psychosis-like behaviors [24]
Summary
Cannabis consumption especially in early adolescence [1], a period of increased vulnerability to its effects, increases the risk of developing schizophrenia [2]. Both cannabis extracts and Δ9tetrahydrocannabinol (THC) can evoke transient psychotic states in healthy subjects [3] and worsen symptoms in schizophrenia patients [4]. Non-hallucinogenic 5-HT2AR agonists exclusively activate the canonical signaling pathway through Gαq/11-proteins. This differential signaling mechanism responsible for the unique effects of hallucinogens is known as biased agonism
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